Safety Study of Zinc Finger Nuclease CCR5-modified Hematopoietic Stem/Progenitor Cells in HIV-1 Infected Patients

The objective of the study is to evaluate the safety and feasibility of giving autologous
SB-728mR-HSPC to HIV-1 (R5) infected patients who are being treated with cART and have
undetectable virus but suboptimal CD4+ cell levels. To strengthen the possibility that
CCR5-disrupted HSPCs engraft, patients will receive either a two- or three-day (Cohort 1 or
Cohort 2) course of busulfan (dose targeting AUC of 4000 µM/day) before being infused with
the genetically modified cells. At 9-12 months after SB-728mR-HSPC infusion, subjects who are
aviremic with CD4 cell counts ≥600 cells/µL and have ≥1% CCR5-modified CD4 cells within the
peripheral blood detected by pentamer PCR will undergo an ATI.

Inclusion Criteria:

- Maximum age 75 years for cohort 1 and 65 years for cohort 2.

- HIV-1 R5 seropositive with no evidence of CXCR4-tropic virus.

- On cART with undetectable HIV-1 (<20 gc/ml HIV-1 RNA) for at least 12 months prior to
screening evaluations.

- CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL.

- No psychosocial conditions that would hinder study compliance and follow-up.

- Absence of clinically significant cardiomyopathy, congestive heart failure.

Secondary Eligibility Criteria (for registration):

- Complete G-CSF/Plerixafor mobilization of HSPC.

- Collect ≥7.5 x 10^6 CD34+ cells/kg in two aphereses.

- The SB-728mR-HSPC product passed all release testing

Exclusion Criteria:

- Use of AZT or maraviroc in the cART regimen.

- History of significant hematologic diseases such as leukemia, myelodysplasia,
coagulopathy, and thromboembolism.

- Any AIDS-related opportunistic infection occurring within the past year such as
tuberculosis, cryptococcosis and for which treatment has been unsuccessful as
determined by the Principal Investigator.

- AIDS-related syndromes, infectious or otherwise, if perceived to cause excessive risk
for morbidity post-HSPC infusion, as determined by the Principal Investigator.

- Patients with active HBV or HCV infection, i.e., HBV DNA and HCV RNA in blood, are
excluded. Those with inactive, but past infection with HBV (positive HBV surface
antigen or HBV surface antibody) or inactive HCV (positive HCV antibody), must have no
cirrhosis, as determined by abdominal ultrasound with elastography.

- Active CMV retinitis or other active CMV-related organ dysfunction.

- CXCR4-tropic virus.

- Pregnant or nursing women.

- Any history of HIV-associated encephalopathy; dementia of any kind; seizures in the
past 12 months; any perceived inability to directly provide informed consent.

- Participants may not be receiving any other investigational agents, or concurrent
biological, chemotherapy, or radiation therapy. Participation in prior investigational
drug or medical device study within the previous 45 days.

- Current or history of immunomodulatory agent or steroid use.

- Prior therapy with HIV vaccine or gene therapy product.

- History of alcohol or substance abuse for the previous 12 months.

- Participants with active malignancies. However, participants with skin cancers, namely
basal cell or squamous cell carcinoma, and malignancies treated with curative intent
having no known active disease present for ≥2 years, may be eligible.